Pyrimedine compounds and method of



Fatented Mar. 16, 1948 PYRIMIDINE COMPOUNDS AND METHOD OF PRQDUCIN GSAME Francis Henry Swinden Curd, Clifiord Gordon Raison, and FrancisLeslie Rose, Blackley, Manchester, England, assignors to ImperialChemical Industries Limited, a corporation of Great Britain No Drawing.Application April 5, 1945, Serial No. 586,820. In Great Britain June 11,1943 16 Claims. (Cl. 260-251) This invention relates to new pyrimidinecompounds and to processes for manufacturing the same and is acontinuation-in-part of our copending application Serial No. 537,536,filed May 26, 1944. The said new compounds, which will be more closelydefined hereinafter, may be described broadly as pyrimidines bearing inthe 2--or 4-position an arylamino group, and in the 4- or 2-position astrongly basic substituent derived from a diamine which is at least inpart aliphatic or alicyclic, and optionally bearing other substituentsin the 5- and 6-p0sitions. They are useful as chemotherapeutic agentsand have properties such as make them particularly valuable asantimalarial agents.

It is an object of this invention to provide new pyrimidine compounds. Afurther object is to provide new chemotherapeutic agents. A furtherobject is to provide new and valuable antimalarial agents. Anotherobject is to provide processes for manufacturing new pyrimidinecompounds. A further object is to provide processes for making newantimalarial agents. Further objects will appear hereinafter as thedescription proceeds. These and other objects are achieved by thefollowing invention.

The said new compounds are pyrimidine derivatives of the formula whereinX is hydrogen or a hydrocarbon radical, Y is hydrogen or a simpleneutral substituent such, for example, as a. hydrocarbon radical, ahalogen atom, an alkoxy or aryloxy or alkylmercapto group, or a cyanogroup, and also X and Y may be joined together to form an alkylenechain, and of the groups G and G, one is an arylamino group which may beunsubstituted or may bear one or more simple non-acidic substituentssuch, for example, as halogen atoms, nitro groups, hydrocarbon radicals(which themselves may optionally bear substituents and which may beattached to the arylamino group directly or through an oxygen or sulphuratom or through an imino, sulphonyl or carbonyl group), cyano groups oresterified carboxyl groups, and the other is a group of the formNR"-A-NRR.' wherein R is hydrogen or an alkyl or simply substituted-alkyl group, for example an alkoxyalkyl or dialkylaminoalkyl group, Ais a linking group which is aliphatic or alicyclic oraliphatic-carbocyclic and may be substituted, for example, byhydrocarbon radicals, hydroxy or, alkoxy groups or dialkylaminoalkylgroups and, where A or part of A is an aliphatic chain, it may beinterrupted by oxygen or sulphur atoms or imino groups, and NRR. is astrongly basic amino or substituted amino group such as alkylamino ordialkylamino or piperidino or other strongly basic nitrogencontainingheterocyclic group,

We make the said new compounds by a process comprising the interactionof a diamine with an appropriate 2- or 4-arylaminopyrimidine bearing thegroups Y and X in the 5- and 6-positions respectively and in the 4- or2-position a labile group such as a halogen atom or a hydrocarbonradical which is attached by means of an ether or thioether linkage, forexample, an alkoxy, aryloxy or alkylmercapto group.

It will be appreciated that in the particular case where the diamine isof the type it is necessary first to protect the free amino group, as byacylation, and then to remove the protecting group after thecondensation with the arylaminopyrimidine compound has been effected.This procedure is, in fact, a particular embodiment of the modifiedprocess hereinafter to be described.

The reaction is conveniently brought about by heating the reagentstogether, optionally in presence of a solvent or diluent. If desired,the arylaminopyrimidine compound or the diamine may be used in the formof a salt, such as the hydrochloride or acetate. Also if desired thereaction may be carried out in presence of an acid-binding agent such assodium hydroxide.

The reagents are conveniently, but not necessarily, used inapproximately stoichiometric proportions. Actually we prefer to useabout 1.25 molecular proportions of the diamine, but. the proportionsare not critical and if desired a large excess of the diamine may beused so that it functions as a solvent or diluent.

The 2- or 4-halogenopyrimidine compounds used as starting materials maybe made by reaction of a halogenating agent such as phosphorus 3ogeno-derivatives with the appropriate hydroxy or mercapto compounds orwith alkali metal derivatives of such compounds.

As examples of suitable arylaminopyrimidine intermediatesthere may bementioned 4-chloro-2-anilino-6-methylpyrimidine,

4-chloro-2- (4'-ch1oroanilino) -pyrimidine,

4 chloro 2 (4' chloroanili'noD 6- methyl pyrimidine,

4-chloro-2- (4'-methy1anilin0-) -pyrimidine,.

4-chloro-2- (4'-methylanilin'o)'--6' methyl'pyrimidine,

4-chloro-2-(4' methoxyanilino) 6- methylpyrimidine,

4 chloro-2 (4 methylmercaptoanilino) 6 methylpyrimldine,

4-chloro-2-(3'-chloroanilino) 6' methylpyrimi dine,

4-chloro-2-(2-chloroani1ino) 6 methylpyrimidine,

4-chloro-2-(3-methylanilinoa 6-- methylpyrimidine,

4-ch1oro-2- (2'-methylanilino) 6 methylpyrimidine;

4-chloro-2-(-2:4'-dichloroanilino) 6 methylpyrimidine,

4-chloro-2-(3'zf-dichloroanilino) 6 methylpyrimidine;

4-chloro-2-(2':5'-dichloroanilino) 6 methylpyrimidine,

4-chloro-2 (2 methyl 4 chloroanilino) 6 methylpyrimidine,

4-chl0ro.- 2 (3 chlbro 4" methylanilino) -6- methylprimidine4-ch10ro-2-(3f':4"-dimetl1ylanilino)- 6 methylpyrimidlne,

4-chloro-2-(3'z5'-dimethylanilino) 6 methylpyrimidine,

4-ch1oro-2-(2'-methoxyanilino) 6 methylpyrimidine,

4-chloro-2-(3:5F-dibromnanilino) 6 methylpyrimidine,

4 -chloro-2 (4' dimethylamino anilino) 6 methylpyrimidine,

4-chloro-2-(4 chloroanilino) 5' bromo 6 methylpyrimidine,

4-chloro-2-(4'-chloroanilino) 6 phenylpyrimidine,

l-chloro-Z-(4'-chloroanilino) 5' plrenylpyrimidine,

4-chl'oro-2-(4methoxyanilino) 5, phenylpyrirm'dine',

4-chloro-2-(4'-chioroanilino) 5 m'ethylpyrimidine,

4'-ch1oro-2-(' chloroanilino) 536'- dimethylpyrimidine,

4-ch1oro-2 (4" chloroanilino)" 5 ethyl 6 methylpyrimidine,

-chloro-Z-(2'5-naphthylamino) 6' methylpyrimidine,

4.-chloro-2-(6 '-bromo 2-' naphthylamino) 6 methylpyrimidine,

4-chloro-2-(6'methoxy-2 -naphthylarnino 6 methylpyrimidine,.

4 -chloro2-(1'-naphthylamino) 6v methylpyrimidine,

4-chloro-2-(4'-chl0ro' 1' naphthylamino 6 methylpyrimidine,

4i-chloro-2 lf-ethoxyanilino) --6 methylpyrimidine,

4.-ch1oro-2-(y bromoanilino') B -methylpyrimidine,

4'-chlor0-2'-(4-'- n- -butylanilino)'- 6 methylpyr-imidine,

4 4-chloro-2-(4-carbomethoxyanlllno) G-methylpyrimidine,4-chloro-2-(4'-phenylanilino) 6 methylpyrimidine,

- 5 phenoxypy- Also the 2-chloro-4-arylamino isomers of the abovecompounds may be used, and likewise the corresponding 4-arylamino-2bromo-, 2-phenoxy-, 2-ethoxy-, 2-methyl-mercapto-, 2-ethylmercaptoand 2phenylmercapto-compounds and their isomers inwhich the 2- and4-substituents are transposed.

As examples of suitable diamines there may be mentioned,ethylenediamine, 2-dimethy1amino ethylamine, 2 diethylaminoethylamine, 3dimethylaminopropylamine, 3-diethylaminopropylamine,4-diethylaminobutylamine, 4 diethylamino-l-methylbutylamine,3-diethylamino -1:2- dimethylpropylamine, S-diethylarnino 2hydroxypropylamine, 2- methylaminoethylamine, 3 butylaminopropylamine, 3diethylarnino ethoxypropylamine, 3-diethylaminoethylmercaptopropylamine,S-diethylamino-l-aminopentane, Z-pyrrolidinoethylamine, 1:3-bis-diethy1amino Z-aminopropane, N-ethyl-N pdiethylaminoethyleethylenediamine, 2 -piperidinoethylamine, 3piperidinopropylamine, p dimethylamino ethoxyaniline,p-diethylaminoethoxyaniline, pdiethylaminoethylmercaptoaniline, 3diethyl amino-Z 2'-dimethylpropylamine, B-di-n-butylaminopropylamine,N-methyl-N-fi-diethylaminoethylpropylenediamine and ,6 piperidino amethyl-ethylamine.

A further feature ofthe' invention is a modified process wherein thebasic substituent NRA- NRR is introduced by stages. Thus theaiylaminopyrimidine compound carrying a labile group in the 2- or4-position is brought into reaction with an amino-compound of the formNHRA-B, where A represents either the whole or a part of the linkinggroup A defined above and where B stands for a reactive group which isthen converted by known methods into the group NRR" or into a groupA"--NRR' such that A and A" together constitute the linking group A. Forexample, the group B" may be a hydroxy group or a derivative thereofwhich is, or isreadily convertible to, a reactive ester thereof, such asa halide, this then being brought into reaction with an amine NHRR or anamino-substituted. amine NH2- "--NRR or a, hydroxyormercapto-substituted amine HO-ANRR or HS -A--NRR (or an alkali metalderivative of such a hydroxy 0r mercapto compound) such that A NH- A-OA' or A'--S--A constitutes the linking group A previously-mentioned.Another alternative is to bring the labile group in the 2- or4'-position of the arylaminopyrimidine compound into reaction with anacylated diamine NHR'A-NHAc and then to hydrolyse off the acyl group.Further, if desired, the free amino group so generated may be modified,as by alkylation, conversion to a heterocyclic group suchas piperidinoor by bringing it into reaction with ahalogeno-substituted amineI-Ia1A"- s NRR such that A'NH-A"' linking group A.

These 2- or i-arylaminopyrimidines carrying a basic substituent in the4- or 2-position and optionally bearing other substituents in the 5- and6-position-s are new compounds. They are strongly basic colourless orpale yellow viscous oils or colourless crystalline solids. When thebases are oils, the picrates, which are crystalline, may be used forpurposes of characterisation. The bases form colourless salts withmineral and organic acids. The salts with mineral acids such as hydrogenhalides, sulphuric and phosphoric acids or with lower organic acids suchas acetic, lactic, tartaric and lower alkanesulphonic acids (e. g.methanesulphonic acid) are water-soluble. The salts with acids of highermolecular weight such as methylene bis-2:3-hydroxynaphthoic acid andmethylene bis-salicylic acid are more sparingly soluble in water.

The following examples illustrate, but donot limit, the invention. Theparts are by weight.

constitutes the Example 1 25.4 parts of 4-chloro-2-p-chloroanilino-6-methylpyrimidine and 14.25 parts of diethylaminoethylamine are stirredand heated together at 120-l30 C. for 6 hours. The resulting melt isdissolved in 500 parts of hot 'dilute hydrochloric acid. After coolingthe solution is basified with caustic soda solution and the base whichis liberated as an oil is extracted with chloroform. The chloroformextract is shaken twice with 250 parts of 5% aqueous acetic acid. Theaqueous extracts are combined, and basified with caustic soda solution.The liberated base is extracted with chloroform and the chloroformextract is dried over potassium carbonate and evaporated. The residualoil is then distilled in vacuo. 4-pdiethylaminoethylamino 2p-chloroanilino-G- methyl-pyrimidine distills over at 224-226 C./0.03mm. It forms a, dipicrate which crystallises from p-ethoxyethanol inthick yellow prisms, M. P. 219220 C.

The base can be converted into its dihydrochloride by dissolving it inan excess of 2-normal hydrochloric acid and evaporating the resultingsolution in vacuo at 50-55 C. The residue is dried and crystallised froma mixture of ethyl alcohol and ethyl acetate and finally from ethylalcohol. 4- p -diethylaminoethylamino-2-pchloroanilino-G-methylpyrimidine dihydrochloride is thus obtained,M. P. 2'70-271 C. (de-' comp.)

In a similar manner from 4-chloro-2-p-chloro-'anilino-S-methylpyrimidine and l-diethylamino- 3-aminopropane there isobtained 4-v-diethylaminopropylamino-Z-pchloroanilino-fi-methylpyrimidine (B. P. 225 C./0.4 mm.). The picratehas melting point 219 C. after recrystallisation from B-ethoxyethanol.The corresponding dihydrochloride melts at 252-254 C. aftercrystallisation from ethanol. It is readily soluble in water.

Likewise from 4-chloro-2-p-chloroanilino-6- methylpyrimidine and1-diethy1amin0-4-amin0- pentane, 4 8 diethylamino a -'methylbutylamino-2p-chloroanilino 6 methylpyrimidine is obtained as a clear yellow viscousoil B. P. 210 C./0.9 mm. The picrate crystallises from a mixture ofB-ethoxyethanol and ethanol in yellow needles, M. P. 168-170 C. Thedihydrochloride melts at 234237 C. after crystallisation from a mixtureof ethanol and ethyl acetate, from which it separates in colourlessneedles.

In a corresponding manner from4-ch1oro-2-pchloroanilino-6-methylpyrimidine andl-diethylamino-l-aminobutane,4-6-diethylaminobutylamino-2-p-chlcroanilino-S-methylpyrimidine isobtained. The dihydrochloride melts at 245- 247 C. after crystallisationfrom ethanol. It forms colourless needles.

Likewise from 4-chloro-2-p-chloroanilino-6- methylpyrimi'dine and1-dim'ethylamino-3-aminopropane there is obtained 4-y-dimethylaminopropylamino-2-p chloroanilino-G-methylpyrimidine, thedihydrochloride of which, crystallised from a mixture of ethanol andethyl acetate, has M. P. 231-234 C.

Similarly by interaction of4-chloro-2-p-ch-loroanilino-fi-methylpyrimidine with l-piperidino-3-aminopropane there is obtained 4- -piperidinopropylamino-2p-chloroanilino 6-methylpyrimidine, the dihydrochloride of which meltsat 289- 292 C.

By interaction of 4-chloro-2-p-.chloroanilino G-methylpyrimidine andp-(p-diethylaminoethoxy) -aniline there is formedi-p-(fi-diethylaminoethoxy)-anilino 2 p chloroanilino-S-methylpyrimidine which after crystallisation from ethanol has M. P.150-152 C.

Again by interaction of 4-chloro-2-p-chloroanilino-fi-methylpyrimidinewith 'l-n-butylamino-3-aminopropane there is obtained4--y-nbutylaminopropylamino 2 p chloroanilino-G- methylpyrimidine, thedehydrochloride of which melts with decomposition at 232-235 C.

Example 2 12.? parts of 4'-chloro-2-p-chloroanilino-6- methylpyrimidine,5.1 parts of Z-dimethylaminoethylamine and 3.75 parts of glacial aceticacid are stirred and heated together for 3 hours at C. The resultingreaction mixture is dissolved in 250 parts of hot dilute hydrochloricacid. After filtering from a little undissolved matter the solutionis'basifi'ed with causticsoda solution and the precipitated oil isextracted with chloroform. The chloroform extract is shaken twice with100 parts of 5% acetic acid, the aqueous extracts combined and basifiedwith caustic soda solution. The base is separated off and dissolved inhot 2-normal hydrochloric acid. On cooling, the dihydrochloride ofl-fl-dimethylaminoethylamin-o 2 p chloroanilino-G-methylpyrimidinecrystallises out. It is filtered ofi and washed with acetone. Byrecrystallisation from ethanol it is obtained as colourless needles,melting point 2l3-215 C. y

Example 3 methylpyrimidine (M, P. l26-127 C. made by heating4-chloro-2-p-chloroani1ino-B-methylpyrimidine withsodium'phenate inphenol) and 7.25 parts of c-diethylaminoethylamine are heated togetherin 45 parts of phenol for 8 hours at l20-l30 C., with stirring. Aftercooling somewhat, the still molten reaction mixture is poured into anexcess of dilute caustic sod-a and the oil which separates out isextracted with chloroform. The chloroform extract is shaken twice with100 parts of 5% aqueous acetic acid and the aqueous extracts arecombined and basified with caustic soda solution. The oil is separatedOE and dissolved -in 100 parts of 7% hydrochloric acid. This solutionisevaporated to dryness under dimini-shed pressure at -50-60" C. and theresidue is crystallised from ethanol whereby 2-p-chloroani- 7iino-i-fi-diethylaminoethylamino -6 methylpy rimidine dihydrcchlorideisobtained; it has M. P.

Working in the same way with 10.4 partsxcf the 'dihydrochloride, or 8.5parts of the monohydrochloride, of p-diethylaminoethylamine instead ofthe 7.25 parts of the free base used'in the process just described,better yields of z-p-chloroanilino-4-5-diethylaminoethylamino-fi-methylpyrimidine dihydrochlor-ide areobtained.

By working in the way described above, but using instead of the 7.25parts of ii-diethylaminoethylamine, 8.1 parts of-diethylaminoprcpylamine, there is obtained2-p-chloroanilino-4-vdiethylaminopropylamino 6 methylpyrimidinedihydrochloride of M. P, '249- 250 C.

Again by using 113 parts of the dihydrechloride or 9.3 parts of themonohydrochloride instead of the 8.1 parts of the free-y-dieth-ylaminopropylamine and working in the manner just describedimproved yields of 2-p-ch1oroanilino-4-- diethylaminopropylamino 6methylpyrimidine dihydroch-lorideare obtained.

Example 4 25.4 parts of 4-chloro-2-p-chloroanilino 6- methylpyrimidineand 12.2 parts of ethanolamine are stirred and heated together at120-130 C. for 10 hours. The resulting melt is heated with 300 parts ofwater and the solidt-hereby obtained is filtered off It is then stirredwith dilute caustic soda solution, again filtered and'washedwell withwater. By crystallisation from methanol2-pchloroanilino-i-p-hydroxyethylamino-G-methyl pyrimidine is obtained,M. P. 157"'158 C. It forms a hydrochloride, M. P. 218 219 C. which issparingly soluble inwater.

14 parts of 2-p-chloroanilino-4-5-hydroxyethylamino-6-methylpyrimidineand 42 parts of phosphorus oxychloride arerefluxed together for 15minutes. The excess of phosphorus -oxyc'hloride is then removed bydistillation in vacuo-at 50-60 C. The residue is added to crushed iceand the mixture is stirred and then allowed to stand for 2 hours. Theproduct which separates is then filtered-off and dissolvcdlin ethanol.Concentrated hydrochloric acid is added to the solution whereupon'2-p-chloroanilino-4-B-chloroethylamino-fi-methylpyrimidinehydrochloride separates in flat needles, M. P. -290-'-291 C.

11.1 parts of 2-p-ch1oroanilino-4-B-chlorcethylamino-6-methy1pyrimidinehydrochloride and 30 parts of diethylamine are heated in a closed vesselat 140, C, for 8 hours. The vessel is then opened and any excess ofdimethylamine is distilled off by heatin the contents to 100 C. for 2hours at atmospheric pressure. The residue is dissolved in 250 parts ofhot dilute hydrochloric acid. After cooling, the solution :is basifiedwith caustic soda solution and the .oily base which is liberated isextracted with chloroform. The chloroform solution is shakentwice with150, parts of acetic acid solution, Theaqueous extracts are combined andbasified with causticsoda solution. The liberated base is extracted withchloroform and the chloroform extract is dried over :anhydrous potassiumcarbonate. The-chloroform is distilled off and the residual oil isdistilled in vacuo. The fraction of B. P. 215-225 C. /0.-01- 0.15 mm. iscollected and consists of4-p-diethylaminoethylamino-Z-p-chloroanilino-G-methyl pyrimidine. Thepicrate of the base melts at 217-219 C. after crystallisation frompaethoxyethanol. 7

Example 5 11.5 parts of4-chloro-2-(4'-dimethylaminoanilino)-6-inethylpyrimidine and -7.1 partsof 'ydiethylaminopropylamine are heated together for 8 hours at -130 -C.After cooling, the reaction mixture is dissolved in dilute hydrochloricacid and. the solution is basified with caustic soda solution. The base,which is liberated as an oil, is extracted with chloroform. Thechloroform solution is extracted twice with 300 parts of 5% 32.3 partsof l-chloro-2-B-naphthylamino-6- methylpyrimidine and 17.4 parts ofdiethylaminoethy-lamine are stirred and heated together at 1'20-130 C.vfor 10 hours. The resulting melt is dissolved in 600 parts of dilutehydrochloric acid. After basification with caustic soda the base, whichis liberated as an oil, is extracted with ether. The ether extract isshaken twice with 250 parts-of'5% aqueous acetic acid, the aqueousextracts are combined and basified with caustic soda solution. The basewhich is liberated is separated ofi and stirred with 300 parts of .2-normal hydrochloric acid. The hydrochloride which separates out isfiltered ofi, washed with acetone and :dried at (SO-65 C. It is purifiedby crystallisation from ethanol. 4-;3-diethylamin0- .ethylaminoQ-finaphth-ylamino 6 methy lpyr- .imid'ine dihydrochloride is thus obtainedas colourless needles, M. P. 252-254 C. (decomp.).

In acorresponding mannerfrom4-chloro-2-flnaphthylamino-G-methylpyrimidine andl-diethylamino-3-aminopropane the 4-y-diethylaminopropylamino 2 pnaphthylamino 6- methylpyrimidine is obtained. The dihydrochloride meltsat 259-2'60 (decomp) after crystallisation from a mixture of .ethanoland ethyl acetate and is readily soluble in water.

Similarly from 4-chloro-2-B-naphthylarnino- 6 methylpyrimidine and 1diethylamino 4- aminopentane the 4-5-diethylamino-e-methylbutylamino-Z-Bnaphthylamino 6 methylpyrimidineis obtained. The dihydrochloride meltsat 268-270 .C. (with decomp.), after crystallisation .from 'a mixture ofethanol and ethyl acetate.

Likewise from 4-chloro-2-Bmaphthylamino-6- methylpyri-midine andl-diethylaminoi-aminobutane the 4 6 diethylaminobutylamino 2 p-:naphthylamino-S-methylpyrimidine' is obtained. The dihydroehloridemelts at 262 263 C. (decomp.) after crystallisation from a mixture ofethanol and ethyl acetate.

Again vfrom 4-chlorc-2-anaphthyiamino-6- methylpyrimidi-ne and 'p-'(,9'- diethylaminoethoxy) -aniline, 4-p- (,c-diethylaminoethoxy)-anilino-2 5-naphthylamino-6methylpyrimidine is obtained. Thedihydrochloride crystallised from ethanol, me-lts at 269-271" :C.(decomp).

Example 7 .11.? parts of 4-.chloro-2-(6'--methoxy 2'-naphthylaminol-.6-methylpyrimidine and 5.7

parts of fl-diethylaminoethylamine are stirred and heated at l20-130 C.for 6 /2 hours. The resulting melt is dissolved in dilute hydrochloricacid and the solution is basified with caustic soda solution. The oilybase which is liberated is extracted with ether. The ether extract isshaken with 250 parts of aqueous acetic acid and the aqueous extract isagain basified with caustic soda solution. The liberated oil isseparated off and dissolved in 60 parts of 2 N hydrochloric acid. Thesolution is evaporated to dryness in vacuo at 50-60 C. and the solidresidue is stirred with acetone and filtered. The solid is washed withacetone and dried at 60-65 C. It is purified by crystallisation fromaqueous ethanol. 4- 3-diethy-iaminoethylamino-2(6'-methoxy-2'-naphthylamino) -6-methylpyrimidine dihydrochloride isthus obtained as colourless needles, M. P. 228- 230 C. (decorno).

In a similar manner from 4-chloro-2-(6-bromo-2'-na;ohthylamino)-6-methylpyrimidine and fl-diethylaminoethylamine, 4 [3diethylaminoethylamino-Z- (6-bromc-2' naphthylamino) -6-methylpyrimidine is obtained. The dihydrochloride forms colourlesscrystals of M. P. 290 C.

(decomp.).

Similarly from l-chloro-Z-(6-bromo-2-naphthylamino)-6-rnethylpyrimidineand 'y-diethylaminopropylamine there is obtained4-v-diethylaminopropylamino-2-(6'-bromo. 2 naphthylamino)-6-methylpyrimidine, the dihydrochloride v of which melts at 259-260 C.(decomp.).

From l-chloro-2 (6' -'bromo 2' naphthylamino)-6-methylpyrimidine and'y-dimethylaminopropylamine there is obtained4-Y-dimethylaminopropylamino)-2 (6' bromo 2'- naphthylaminc)-6-rnethylpyrimidine, the dihy-. drochloride of which melts at 234-236C. (decomp.). c

From l-chloro 2 (6 bromo 2' naphthylamino) 6 methylpyrimidine and 5dimethylaminoethylamine there is obtained 4-E3-dimethylaminoethylamino-2(6' bromo 2' naphthyl-.

amino) -6-methylpyrimidine, the dihydrochloride of which melts at276-278" C. (decomp).

From 4-ch1oro-2 (6' bromo 2' naphthylamino) -6-methy-lpyrimidine andY-piperidinopropylamine there is obtained4-v-piperidinopropylamino-2-(6' bromo 2' naphthylamino) -6-methylpyrimidine, the dihydrochloride of which melts at 256-258 C.

Example 8 9.75 parts of 4-chloro-2-(3'-chloroanilino)-G-methylpyrimidine and 6.25 parts of 'Y-diethylaminopropylamineare'heated together at 120- 130 C. with stirring for 8 hours. Threaction mixture is then dissolved in 200 parts of dilute hydrochloricacid, cooled and basified with caustic soda solution. The oily basewhich is precipitated is extracted with chloroform and this chloroformsolution extracted twice with 100 parts of 5% aqueous acetic acid. Theacetic acid extracts are combined and basified with caustic sodasolution. The liberated base is again extracted with chloroform and thechloroform solution extracted with Z-normal hydrochloric acid (twoextraction, using 150 parts and 100 parts). The hydrochloric acidextracts are combined and evaporated in vacuo at 60-65" C.i-r-diethylaminopropylamino 2 (3 chloroanilino) 6- methylpyrimidinedihydrochloride remains as'a crystalline solid. After crystallisationfrom ethanol, it forms. colourless needles of M. P. 215- 217 C.

In a similar way, from 4-chloro-2-(2'-chloroanilino) 6 methylpyrimidineand 7 diethylaminopropylamine there is obtained 4-y-diethylaminopropylamino 2 (2 chloroanilino)-6- methylpyrimidine, thedihydrochloride of which melts at 238239 C.

Likewise by interaction of 4-chloro-2- (2'- chloroanilino) 6methylpyrimidine and c-diethylaminoethylamine, 4 ,6diethylaminoethylamino-Z- (2'-chloroanilino) -6- methylpyrimidine isobained. Its dihydrochloride has M. P, 251- 253 Example 9 19 parts of4-chloro-2-(2':4'-dichloroanilino)- G-methylpyrimidine and 10.8 parts ofY-diethylaminopropylamine are intimately mixed and heated together for 8hours at 120-130 C. After cooling, the reaction mixture is dissolved indilute hydrochloric acid. It is then basified with caustic soda solutionand the liberated base is extracted with chloroform. The chloroformsolution is extracted twice with 250 parts of 5% aqueousacetic acid andthe acid extracts are combined and basified with caustic soda solution.The base thus liberated, which is 4-'y-diethylaminopropylamino-Z- (2':4'-dichloroanilino) 6 methylpyrimidine, is separated ofi and purifiedby distillation under high vacuum. It has B. P. 208-210 C./0.02 mm. andforms a picrate which, after crystallisation from .c-ethoxyethanol,melts at 210-211 C.

To form the dihydrochloride the base is dissolved in 2-normalhydrochloric acid and con- 1 centrated hydrochloric acid is addedwhereupon the hydrochloride slowly crystallises out. It may be furtherpurified by dissolving it in water and reprecipitating by addition ofconcentrated hydrochloric acid. It then melts at 208-210 C.

In a similar manner, from 4-chloro-2-(3':4'- dichloroanilino) 6methylpyrimidine and '7- diethylaminopropylamine there is obtained 4-7-diethylaminopropylamino-Z (3z4' dichloroanilino)-6-methylpyrimidine. Itsdihydrochloride has M. P. 237-239 C.

Also from 4-chloro-2- (2' :5'-dichloroanilin0) B-methylpyrimidine and'Y-diethylaminopropylamine there is obtained4-v-diethylaminopropylamino-2- (2' :5 -dichloroanilino)-6-methylpyrimidine of M. P. 98-100 C. (decomp.). The dihydrochloridemelts at 248-250 C.

Example .10

25 parts of 4-chloro-2-(4-methoxyanilino)-6- methylpyrimidine and 14parts of ,B-diethyh amlnoethylamine are mixed and heated together at120-130 C. for 6 hours. After cooling the reaction mixture is dissolvedin dilute hydrochloric acid. It is then basified with caustic sodasolution and the liberated base is extracted with ether. The ethersolution is extracted twice with 200 parts of 5% acetic acid, the acidextracts combined and basified with caustic soda solution. The base isseparated off and dissolved in parts of 2-normal hydrochloric acid andthe solution evaporated to dryness in vacuo at 50-60 C. Thedihydrochloride of 4-p-diethylaminoethylamino 2 (4 methoxyanilino) 6-methylpyrimidine which remains is purified by crystallisation from ethylalcohol and then has M. P. 231-232 C.

In a similar way from 4-chloro-2-(2-meth0XY- aniline) 6 methylpyrimidineand 3 diethylaminoethylamine there is obtained4-,B-diethylaminoethylamino 7 2 (2' methoxyanilino) 6- methylpyrimidine,the dihydrochloride of which has M. P. 2'72-2'73 C.

From 4-chloro-2- (4'-methylan'llino) -6-methylpyrimidine ande-diethylaminoethylamine there is obtained4-5-diethylaminoethylamino-2-(4'- methylanilino)-6 -methylpyrimidine,the dihydrochloride of which has M. P. 216-218 C.

' From 4-chloro-2-(4-methylmercapto-anilino) 6 methylpyrimidine and 8-diethylaminoethyl-- tained 4 p3 diethylaminoethylamino 2. (2.-

methylanilino) 6 -methylpyrimidine, the dihydrochloride of which has M.P. 237-238 C.

From l-chloro-Z- 3'-methylanilino) -6-methylpyrimidine andfi-diethylaminoethylam-ine there is obtained4-,8-diethylaminoethylamino-2-(3'- methylanilino)-6 methylpyrimidine,the dihydrochloride of which has M. P. 272 -27? C.

From 4-chloro-2- (4"-ethoxyanilino) -6-methy1' pyrimidine andp-diethylaminoethylamine there is obtained 4 pdiethylaminoethylamino-Z-(4'- ethoxyanilino) -6-methylpyrimidine, thedihydrochloride of which has M. P. 211-213 C.

From 4 chloro-Z-wnaphthylamino-fi-methy1- pyrimidine andp-diethylaminoethylamine there is obtained 4 8diethylaminoethylamino-Zwnaphthylamino-6 -methylpyrimicline. thedihydrochloride of which has M. P, 275-276 C. (de:- comp).

From l-chloro-Z-( l' chloro I naphthylamino) -6-methylpyrim-idine andp-diethylaminoethylamine there is obtained 4-p-diethylaminoethylamino-2-(4' -chloro-lnaphthylamino) -6-' methylpyrimidine, the dihydrochlorideof which has M. P. 294-295 C.

Example 11,

15 parts of 4-chloro-2-(2'-methy1 4"-chloroanilino) -6-methy1pyrimidineare heated with. 13 parts of v-dibutylaminopropylamine at 120-130 C. for8 hours. The reaction mixture is dissolved in dilute hydrochloric acidand basified with caustic soda solution. The liberated base is extractedwith chloroform, the solution is dried and the chloroform distilled offin vacuo. The base then remaining is distilled in vacuo. It is4-y-dibutylamino propylamino-2-(2'-methyl-4'- chloroanilino)-6-methylpyrimidine. It has a boflin'g point of 236 C./0.06 mm. andforms a picrate which. after crystallisation from a mixture ofs-ethoxyethanol and ethanol, melts at 157-159 C. To make thedihydrochloride the base is dissolved in 2-normal hydrochloric acid andthe solution is evaporated to dryness in vacuo. The residue iscrystallised from a mixture of ethyl alcohol and ethyl acetate. wherebyl-y-dibutylaminopropyl amino-z- (2-methyl-4'-chloroanilino)-6-methylpyrimidine dihydrochloride is obtained, M. P. 204-205" C.

In a similar way from 4-chloro-2-(2' methyl-4'-ch1oroanilino)-6-methylpyrimidine and -diethylaminopropylamine thereis obtained 4-- -diethylaminopropylamino-Z (2' methyl-4 -chloroanilino)-6-methylpyrimidine, the dihydrochloride of which has M. P. 150-152 C.

Similarly from4-chloro-2-(3'-chloro-4'-methylanilino)-6-methylpyrimldine and'ydiethylaminopropylamine there is obtainedi-y-diethylairflnopropylamino-Z- (3'-chloro 4' methylanilino)-6-methylpyrimidine, the dihydrochloride of which has M. P. 230-232 C.

From 'y-diethylaminopyropylamine and 4- chloro-2-(3':4- dimethylanilino)6 methylpyrimidine there is obtained4-Y-diethylaminopropylamino-2-(3':4'-dimethylanilino) 6methylpyrimidine, the dihydrochloride of which has M. P. 222-224 C.

From the same diamine and the isomeric 4- chloro-2- (3' :5'-dimethylanilino) 6 methylpyrlmidine there is obtained4-y-diethylaminopropylamino-2- (3' 5-dimethylanilino)-6-methylpyrimidine, the dihydrochloride of which has M. P. 306-308 C.

From the same diamine and 4-chloro-2-(3:5- dibromoanilino)-6-methylpyrimidine there is obtained 4- -diethylaminopropylamino-2- (3':5 dibromoanilino)-6-methylpyrimidine, the dihydrochloride of which hasM. P. 264-266 C.

From the same diamine and 4-chloro-2-(4'-bromoanilino)-6-methylpyrimidine there is obtained4-'y-diethylaminopropylamino-2-(P-bromoanilino) -6methylpyrimidine,thedihydrochloride of which has M; P. 2 2 7 C.

From 4-chloro-2- (4'-butylani1ino) -6-methylpyrimidine and'y-diethylaminopropylamine there is obtained 4---diethylaminopropylamino-2-(4- butylanilino)-6-methylpyrimidine, thedihydrochloride of which has M. P. 188-l90 C.

From 4-chloro-2- (4'-carbomethoxyanilino) -6- methylpyrimidine and-diethylaminopropylamine there is obtained 4--diethylaminopropylamino-Z- (4'-carbomethoxyanilino) G-methylpyrimidine,the dihydrochloride of which has M. P. 263-265 C.

From 4'-chloro-2- (4'-phenylanilino) -6-methylpyrimidine andv-diethylaminopropylamine there is obtained 4-7-diethylaminopropylamino-2- (4f'-phenylaniIino-) -6-methylpyrimidine, the dihydrochloride ofwhich has M. P. 244-246 C.

From 4-chl'oro-2- (4-nitroanillno) -6-methylpyrimidine andy-diethylaminopropylamine there is obtained4-'y-diethylaminopropylamino-2-(4'- nit'roanilino) -6-methylpyrimidine,the dihydrochlorlde of which has M; P. 226-232 C.

From the same diamine and 4-chloro-2-(4-cyanoanilino)-6-methylpyrimidine there is obtained 4--diethylaminopropylamino-Z-(4'-cy anoanilino)-6-methylpyrimidine, thedihydrochloride of which has M. P. 249-251 C.

Example 12 6.3 parts. of 2-p-chloroanilino-i-chloro-6- phenylpyrimidineare stirred and heated at C. for 8 hours with 3 parts ofB-diethylaminoethylamine. The resulting melt is dissolved in 500 partsof hot dilute hydrochloric acid and basified. with caustic sodasolution. The base thus liberated is extracted with chloroform and thechloroform extract is evaporated. The oily residue is dissolved in 100parts of 5% aqueous acetic acid. filtered and the filtrate basified withcaustic soda solution. The base which is again liberated is extractedwith ether and th ether extract is dried over anhydrous potassiumcarbonate. After distilling off the ether, the oily residue isdissolved-in hot 2-norma1 hydrochloric acid. On cooling, 2-p-chloroanilino-4-p-diethylaminoethylamino-B-phenylpyrimidinadihydrochloride separates out and i filtered off. After crystal- 13'lisation from ethanol it has M. P, 277279 C. (decomp.).

In a similar way from 2-p-methylanilino-4- chloropyrimidine andfl-diethylaminoethylamine there is obtained2-p-methylanilino-4-c-diethylaminoethylaminopyrimidine, thedihydrochloride of which has M, P. 220-221 C.

Similarly from Z-p-chloroanilino-4-chloropyrimidine and7-diethylaminopropylamine there is obtained2-p-chloroanilino-4-'y-diethy1aminopropylaminopyrimidine, thedihydrochloride of which has M. P. 208-210 C.

From Z-p-chloroanilino-4-chloro-5 G-dimethylpyrimidine andv--diethylaminopropylamine there is obtained2-p-chloroanilino-l-y-diethylaminopropylamino-5 6 -dimethylpyrimidine,the dihydrochloride of which has M. P. 277 -279 C. (decomp.).

Example 13 10.5 parts of 2-p-chloroanilino-4-chloro-5-ethyl-S-methylpyrimidine and 4.1 parts of fi-dimethylaminoethylamine arestirred and heated together at l25-135 C. for 8 hours. The resultingmelt is dissolved in 500 parts of hot dilute hydrochloric acid andbasified while still hot with caustic soda solution and the base thusliberated is extracted with chloroform. The chloroform extract is shakenthree times with 200 parts of 5% aqueous acetic acid and the acetic acidextracts are combined and basified with caustic soda solution. Theliberated base is extracted with chloroform, the chloroform solution isdried over anhydrous potassium carbonate and the chloroform is distilledoil. 2-p-chloroanilino-4- pdimethylaminoethylamino-5-ethy1-6-methylpyrimidine remains as a solid.It may be purified by crystallisation from petroleum ether (B. P. 60-80C.) when it melts at 115-116 C.

To make the dihydrochloride the crude base is dissolved in hot 2-normalhydrochloric acid. On cooling 2-p-chloroanilino-4 ,8dimethylaminoethylamino-5-ethyl 6 methylpyrimidine dihydrochloridecrystallizes out. It may be purified by recrystallisation from ethanoland then melts at 262 C. with decomposition.

By the reaction of the same chloro compound with8-diethylaminoethylamino, 2-p-chloroanilino-4-fl-diethylaminoethylamino5 ethyl 6- methylpyrimidine is obtained, M. P. 92-94 C. afterrecrystallisation from petroleum ether (B. P. 40-60 0.). Thedihydrochloride, recrystalised from a mixture of ethanol and acetone,has M. P. 258-260 C.

Similarly by using 'y-dimethylaminopropylamine as the diamino,2-p-chloroanilino-4-ydimethylaminopropylamino-S-ethyl 6 methylpyrimidineis obtained. After crystallisation from petroleum ether (B. P. 100-120C.) it has M. P. 126-12S C. The dihydrochloride after crystallisationfrom a mixture of ethanol and acetone has M. P. 244-246 C.

Further, by interaction of 2-p-chloroanilino-4-chloro-5-ethyl-S-methylpyrimidine and y-diethylaminopropylamine thereis obtained 2-pchloroanilino-4-y-diethylaminopropylamino 5-ethyl-S-methylpyrimidine which on crystallisation from petroleum etherseparates in colourless laminae, M. P. 108-109 C. The dihydrochloridecrystallises from ethanol, and then melts at 272- 274" C. Withdecomposition.

Example 14 10.9 parts of 2- p-chloroanilino-4-chloro5- bromo-fi-methylyrimidine and 5.3 parts of Y-di 1'4 ethylaminopropylamine are stirredand heated together at l25-135 C. for 8 hours. The resulting melt isdissolved in hot dilute hydrochloric acid. The acid solution is basifiedwith caustic soda solution and the base so liberated is extracted withether. The ether extract is shaken twice with parts of 5% aqueous aceticacid. The combined acetic acid extracts are basified with caustic sodasolution and the liberated base again extracted with ether. After dryingover anhydrous potassium carbonate, the ether is distilled off.2-p-chloroanilino-4-'y-diethylaminopropylamino-5-bromo 6methylp-yrimidine remains. This can be purified, if desired, bycrystallisation from petroleum ether (B. P. 6Q-80 C.) and then has M. P.94-96 C.

To form the dihydrochloride the crude base is dissolved in hot 2-norma1hydrochloric acid. On cooling2-p-chloroanilinol-y-di-ethylaminopropylamino-5-bromo-6-methylpyrimidinedihyd-rochloride is obtained. After crystallisation from ethanol it hasM. P. 236-238 C.

In a similar way from 2-p-chloroanilino-4- chloro-5-phenylpyrimidine andfi-diethylaminoethylamine there is obtained 2-p-chloroanilino-4-c-diethylaminoethylamino 5 phenylpyrimidine which has M. P. 152-153 C.Its dihydrochloride has M. P. 264-266 C. (decomp.).

From 2-p-chloroanilino-4-chloro-5-phenylpyrimidine andy-diethylaminopropylamine there is obtained2-p-chloroanilino-4-'y-diethylaminopropylamino-5-phenylpyrimidine of M.P. 155- 156 C. The dihydrochlo'ride melts at 264-266 C., after softeningat 262 C.

From z-p-methoxyanilino-i-chloro-5-phenylpyrimidine andp-diethylaminoethylamine there is obtained2-p-methoxyanilino-4-p-diethylaminoethylamino-5-phenylpyrimidine of M.P. 158- 159 C. The dihydrochloride has M. P. 209-211 C. (decomp.).

From 2-p-chloroani1ino 4 chloro-pyrimidin and the same diamine there isobtained 2-pchloroanilino-4-;8-diethylaminoethylamino pyrimidine of M.P. 7l-'72 C. The dihydrochloride has M. P. 237-2383 C.

From 2-p-chloroanilino-4-chloro-5-methylpyrimidine and the same diaminethere is obtained 2-p-chloroanilino-4-p diethylaminoethylaminm5-methylpyrimidine of M. P. 106-108 C. The dihydrochloride has M. P. 269C. (decomp.).

From 2-p-chloroanilino-4-chloro-5 6-dimethylpyrimidine and 13diethylaminoethylamine there is obtained2-p-chloroanilino--fi-diethylaminoethylamino-S:S-dimethylpyrimidine ofM. P. l00-102 C. The dihydrochloride has M, P. 270-271 C.

From 2-p-chloroanilino-4-chloro-5-phenoxypyrimidine andB-diethylaminoethylamine there is obtained2-p-chloroanilino-4-5-diethylaminoethylamino-5-phenoxypyri-midine of M.P. 84- 85 C.

Example 15 13.2 parts of v2-p-c hloroanilino-4 -ethoxy-6-methylpyrimidine and 9.84 parts of 'B-diethylamino-l-aminopropanemonohydrochloride are mixed and heated with stirring at -195 C. for

6 hours. After cooling the reaction mixture is dissolved in warm dilutehydrochloric acid and the resulting solution basified with caustic soda.The base which is liberated is extracted with ether and the ethersolution is extracted with 5 acetic acid. The acetic acid extract isbasified with caustic soda and the liberated base is extracted withchloroform. The chloroform solution is dried, the chloroform isdistilled 01? and the residue is dissolved in 2-norma1 hydrochloricacid. The solution is evaporated to dryness in vacuo at 50-60. C. andthe residue, after drying, is crystallised' twice from. ethanol. Thereis thus obtained 4-' -diethylaminopropylamino-2-p-chloroanilino-B-methylpyrimidine dihydrochloride, M. P. 250- 252 C.

Example 16 8.6 parts of2-p-chloroanilino-4-chloro-5-benzyl-6-methylpyrimidine and 3.25 parts ofp-diethylaminoethylamin are stirred and heated to-' gether at125--135 C.for 8 hours. While still hot, the melt is dissolved in 400 parts ofdilute hydrochloric. acid and the hot solution is basified with causticsoda solution. The base which separates out is filtered off, washed withwater and dissolved in 500 parts of 5% aqueous acetic acid. The acidsolution is clarified with charcoal and then again made alkaline withcaustic soda solution. The base which is precipitated is extracted with,chloroform. The chloroform solution is dried and the chloroform isdistilled off. The

crude2-p-chloroanilino-4-p-diethylaminoethylamino-5-benzyl-G-methylpyrimidinewhich remains is crystallised from petroleum ether (B. P. 60-80 C.) andthen has M. P. ll4-115 C.

To make. th dihydrochloride the crude base is dissolved in hot 2-normalhydrochloric acid; on cooling the dihydrochloride crystallizes out. Itmay be purified by recrystallisation from ethanol and then has M. P.255-266 C. (decomp.)

In a similar way, from the same chloropyrimidine andv-diethylaminopropylamine there is obtained 2-p-chloroanilino-4.-'-diethylaminoethylamino-5benzy1-6-methyipyrimidine of M. P. 104-105 C.The dihydrochloride has M. P. 274-276 C.

From the same chloro-pyrimidine and 7-61- methylaminopropylamine thereis obtained 2-pchloroanilino 4 y-dimethylaminopropylamino-5-benzyl-fi-methylpyrimidine of M. P. 112-114 C.

From 2-p-chloroanilinol-chloro-5-benzyl-6- methylpyrimidine and5-diethylamino-2-aminopentane there is obtained2-p-chloroanilino-4-tdiethylamino-a-methylbutylamino-5-benzyl 6methylpyrimidine, the dihydrochloride of which has M. P. 242-244 C.

Example 17 9.8 parts of 2-p-chloroanilino-4-chloro-5:6:7:8-tetrahydroquinazoline and 4.83 parts of ,B-diethylaminoethylamineare stirred and heated together at 125l35 C. for 8 hours. After cooling,the reaction mixture is dissolved in dilute hydrochloric acid and thesolution is basificd with caustic soda. The base which is liberated isextracted with chloroform and the chloroform solution is evaporated todryness. The residue is extracted with 400 parts of 5% aqueous aceticacid and the base is again liberated from the extract by addition ofcaustic soda solution and then extracted with ether. The ether solutionis dried over anhydrous sodium sulphate and the ether is distilled 01f.2-p-chloroanilino-4-pdiethylaminoethylamino 5:6:'7:8tetrahydroquinazoline remains. It may be purified by crystallisationfrom petroleum ether, from which it separates in colourless prisms of M.P. 132-134 C.

The dihydrochloride can readily be made in the usual mannerand whencrystallised from a mixture of ethanol and ethyl acetate has M. P.224-226 C.

- In a similar way, from the same chloro-compound and-dimethylaminopropylamine there is obtained2-p-chloroanilino-4-'y-dimethylaminopropylamino 5:6:718tetrahydroquinazoline which crystallises from petroleum ether (B. P.-120 C.) in the form of colourless flat prisms of M. P. 125-l27 C. Thedihydrochloride, crystallised from a mixture of ethanol and ethylacetate,has M. P. 290 C. (decomn) Again, from the same chloro-compoundand -diethylaminopropylamine there is obtained 2-pchloroanilino 4 'ydiethylaminopropylamino- 5 6 7 :8-tetrahydroquinazoline whichcrystallises from petroleum ether (B. P. 100-120 C.) in colourless fiatprisms of M. P. 138-140 C. The dihydrochloride, when crystallised from amixture of ethanol and ethyl acetate, has M. P. 202-204 C.

Example 18 5 parts of 2-chloro-4-p-chloroanilino-G-methylpyrimidine and3.2 parts of -diethylaminopropylamine are heated together at -130 C. for8 hours. The'reaction mixture is cooled somewhat and dissolved inv hotdilute hydrochloric acid. The solution is cooled and basified withcaustic soda and. the base which is liberated is extracted withchloroform. The chloroform solution is twice extracted with 5% aqueousacetic acid, the acid extracts are combined and basified with causticsoda and the base is again extracted with chloroform. The chloroformsolution is dried and the chloroform is distilled off. The oily residueis the base, 2-y-diethylaminopropylamino-4-p-chloroanilino-6-methylpyrimidine. It readily forms a picrate whichcrystallises from pethoxyethanol and melts at 212-213 C.

The base may be converted to the dihydro chloride by dissolving it inhot 2-normal hydrochloric acid and cooling the solution. Thehydrochloride separates out and is filtered off, washed with acetone anddried. There is thus obtained 2-'-diethylaminopropylamino-4-p-chloroanilino- G-methylpyrimidinedihydrochloride which may be crystallised from a mixture of methylalcohol and ethyl acetate and then has M. P. 268-270 C.

Example 19 11.4 parts of 2-p-chloroanilino-4-chloro-5:6-dimethyl-pyrimidine and 5.5 parts of 7-dimethylaminopropylamine arestirred and heated together at 135 C. for 8 hours. The melt is cooledand dissolved in dilute hydrochloric acid and the solution is madealkaline by addition of caustic soda solution. The crude base which isliberated is extracted with chloroform and the chloroform solution isevaporated to dryness. The residue is extracted with 400 parts of 5%aqueous acetic acid and the base is again liberated by addition ofcaustic soda solution and extracted With chloroform. The chloroformsolution is dried over anhydrous sodium sulphate and the chloroform isdistilled oil. 2-p-chloroanilino-4-y-dimethylaminopropylamino-5:6dimethylpyrimidine remains. After crystallisation from petroleum ether(B. P. 6080 C.) it has M. P. 116118 C. The dihydrochloride, crystallisedfrom ethanol, has M. P. 238-240 C.

In a similar way from 2-p-chloroani1ino-4- chloro 5 ethyl 6methylpyrimidine and 2 amino-5-diethylaminopentane there is obtained2-p-chloroanilino-4-6-diethylamino amethylbutylamino-B-ethyl-G-methyl-pyrimidine, which is an oil. Thedihydrochloride, obtained in the usual manner and purified bycrystallisation from a mixture of ethanol and ethyl acetate has M. P.231-233' C.

17 Example 20 12.7 parts of 2-p-chloroanilino-4-chloro-6-methylpyrimidine and 8.1 parts of fi-diethylaminoethyl methylamine areheated together for 8 hours at 120130 C. The reaction mixture isdissolved in hot dilute hydrochloric acid. The solution is filtered,cooled and basified with caustic soda solution and the base is extractedwith chloroform. The chloroform solution is extracted twice with aqueousacetic acid, the acid extract is basified with caustic soda, and thebase is again extracted with chloroform. The solution is dried and thesolvent is distilled oil. The residual oil is the base,2-p-chloroanilino-4- (,6-diethylaminoethyl-methylamino) 6methylpyrimidine. It forms a picrate which crystallises fromfi-ethoxyethanol with M. P. 204206 C.

The base is converted to the hydrochloride by dissolving in Z-normalhydrochloric acid and evaporating to dryness in vacuo. After drying, the2-p-chloroanilino- 4 -(;3 diethylaminoethylmethylamino) 6methylpyrimidine dihydro chloride is crystallised from a mixture ofalcohol and ethyl acetate; it has M. P. 257258 C.

Example 21 13.94 parts of 4 chloro 2(6'- bromo 2-naphthylamino)-6-methylpyrimidine and 8.95 parts of3-di-n-butylamino-propylamine are heated together with stirring at120-130 C. for 6 hours. After cooling, water and sufiicient caustic sodato make the mixture alkaline are added and the mixture is stirred withchloroform until all is dissolved either in the Water or in thechloroform. The chloroform layer is then separated and the chloroform isdistilled off. The residue is extracted with 200 parts of 5% acetic acidand the extract is shaken twice with ether, the ether extracts beingdiscarded. 0n the addition of 50 parts of concentrated hydrochloric acidto the acetic acid solution, 4-y di-n butylaminopropylamino-2-(6'-bromo2-' naphthylamino)-6-methylpyrimidine dihydrochloride is precipitated ina crystalline condition. It is filtered off, washed first with 2-normalhydrochloric acid and then with acetone. After drying at 60-65 C. it isfurther purified by crystallisation from a mixture of ethanol and ethylacetate when it is obtained as colourless needles, M. P. 230-232 C.(with efiervescence).

Example 22 12.7 parts of 4-chloro-2-p-chl0roanilino-6- methylpyrimidineand 11.6 parts of y-di-n-butylamino-propylamine are stirred and heatedtogether at 125-135 C. for 8 hours. The reaction mixture is dissolved inwarm dilute hydrochloric acid and the solution is basified with causticsoda while still warm. The base which is precipitated is extracted withchloroform and the chloroform solution is dried over potassiumcarbonate. The chloroform is then distilled off and the residual oil isdistilled in vacuo. The fraction of B. P. 224-228 C./0.04 mm. iscollected and. consists of 4-y-di-n-butylaminopropylamino-2-p-chlor0-anilino-6-methylpyrimidine.

For conversion to the hydrochloride the base is dissolved in warm dilutehydrochloric acid and to the solution an excess of concentratedhydrochloric acid is added. The hydrochloride is precipitated and isfiltered ofi, dried and crystallised from a mixture of ethanol and ethylacetate. It is thus obtained in the form of the dihydrate whichpossesses no sharp melting point; it softens 18 Example 23 12.7 parts of2-p-chloroanilino-4-chloro-6-' methylpyrimidine and 8 parts offi-piperidinoethylamine are heated together for 8 hours at 120-130 C.The reaction mixture is cooled, dissolved in hot dilute hydrochloricacid and basified with caustic soda solution. The base which isliberated is extracted with ether, the ether solution is in turnextracted with 5% acetic acid and the acid extract is basified withcaustic soda solution. The base is then extracted with chloroform, thesolution is dried and the solvent is distilled off.2-p-chloroanilino-4-fi-piperidinoethylamino-G-methylpyrimidine remains.It is an oil; it forms a picrate which, crystallised fromfi-ethoxy-ethanol, has M. P. 230-231 C. The dihydrochloride is obtainedby dissolving the base in hot Z-normal hydrochloric acid; thehydrochloride crystallises out on cooling. It is filtered ofi, washedwith acetone and dried, and then crystallised from alcohol. It then hasM.P. 288-290 C.

In a similar manner from the same chlorocompound and the appropriatediamine there are obtained 2-p-chloro-anilino 4 Bpyrrolidinoethylamino-6-methylpyrimidine dihydrochloride, M. P. 280-282C., and 2-p-chloroanilir'1o-4-fipiperidino u methylethylamino 6methylpyrimidine dihydrochloride, M. P. 254-256 C.

Example 24 12.7 parts of 2-p-chloroanilino-4-chloro-6- methylpyrimidineand 10.9 parts of Y-(fi-diethylaminoethoxy)-propylamlne are heatedtogether for 8 hours at 120-130 C. The reaction mixture is thendissolved in hot dilute hydrochloric acid, cooled and basified withcaustic soda solution. The base which is liberated, is extracted withchloroform, the chloroform solution is in turn extracted with aqueous 5%acetic acid and the acid extract is basified with caustic soda solution.The base is again extracted with chloroform, the solution is dried andthe chloroform is distilled ofi. The oil remaining is Z-p-chloroanilino4 'y -(p diethylaminoethoxy) propylamino-G-methylpyrimidine. It forms apicrate which when crystallised from a mixture of pethoxyethanol andethanol has M. P. 142-144 C. The dihydrochloride is made by dissolvingthe base in 2-normal hydrochloric acid and evaporating the solution todryness in vacuo. After drying it is crystallised from a mixture ofethyl alcohol and ethyl acetate and then has M. P. 192-193 C.

In a similar manner, from the same chlorocompound and N-methyl-N pdiethylaminoethyl-trimethylenediamine there is obtained 2-pchloroanilino-4-'y-(N-methyl-N-fi-diethylaminoethyl-amino) propylamino-6-methylpyrimidine. The picrate has M. P. 206-208 C. and thetrihydrochloride, made by dissolving the base in 2-normal hydrochloricacid, evaporating to dryness and crystallising the residue from ethanol,has M. P. 234-236 C.

Similarly from the same chloro-compound andbis-(fl-diethylaminoethyl)amine there is obtained2-p-chloroanilino-4-bis- (p-diethylaminoethyl)-amin0-6-methylpyrimidine.The picrate has M. P. 192-194 C. and the trihydriodide, made bydissolving the base in alcohol, acidifying with aqueous 55% hydriodicacid, evaporating to dryness in vacuo and crystallising from ethanol hasM. P. 241-243 C.

at about 120 c. and finally melts at 154-164 c. in from the samechloro-com u deni b chloroanilino-G-methylpyrimidine 19(diethylaminomethyl) -methylamine there is obtained 2-p-chloroanilino 4-(bis-diethylaminomethyl-methylamino) -6-methylpyrimidine. The picratehas M. P. l81-183 C. and the trihydriodide M. P. 240-24l C.

By working in accordance with the methods described above the followingfurther compounds are obtained, namely:

Example 25.-2-pl-diethylaminoethylamino-4- p chloroanilino 6methylpyrimidine, M. P. 96-97 C. Y

Example 26.2-Y-piperidinopropylamino-l-pdihydrochloride, M. P. 278-280C.

Example 27.2e' -dimethylaminopropylamino-4-p-chloroanilino-6-methylpyrimidine dihydrochloride, M. P. 270 C.

Example 28.2 8-diethylaminoethylamino-4-p-methoxyanilino-6-methylpyrimidine dihydrochloride, M. P. 216-218 0.

Example 29.-2-fl-diethylaminoethylamino-4- p methylanilino 6methylpyrimidine, M. P. 6668 C.

Example 30.2-6-diethylaminobutylamino-4- p chloroanilino 6methylpyrimidine dihydrochloride, M. P. 197-198 C.

Example 31.2-6-diethylamino-a-methylbutylamino-4-p-chloroanilino-G-methylpyrimidinedihydrobromide, M. P. 200201 C.

Example 32.-2-7-N-methyl-N-isopropylaminopropylamino-4-p-chloroanilino-S-methylpyrimidin-e dihydrochloride, M. P. 274276 C.

Example 33.2 -7- dibutylaminopropylamino-4-p-chloroanilino-6-methylpyrimidine dihydrochloride, M. P. 1711'73 C.

Example 34.2 -adimethylaminobutylamino- 4 p chloroanilino 6methylpyrimidine, M. P. 156-158 C.

Example 35.2 -Y- butylaminopropylamino-4- p chloroanilino 6methylpyrimidine dihydrochloride, M. P. 301-303 C.

Example 36.--2-6-dibutylaminobutylamino-4- p chloroanilino 6methylpyrimidine dihydrochloride, M. P. 125-127 C.

Example 37.2-p-chloroanilino-4-'y-N-methyl- Nisopropylaminopropylamino-6-methylpyrimidine dihydrochloride, M. P.251-252 C.

Example 38.2-7-dibutylaminopropylamino-4- p-chloroanilino-5G-dimethylpyrimidine dihydrochloride, M. P. 204-205 C.

Example 39.2-p-chloroanilino-4-y-dimethylaminopropylamino- 5:6-trimethylenepyrimidine, M. P. 142-144 C.

Example 40.2-p-diethylaminoethylamino-4- p nitroanilino- 6methylpyrimidine, M. P. 160-l61 C.

Example 41 .2 y piperidinopropylamino-4- p nitroanilino 6methylpyrimidine, M. P. 174-175 C.

Example 42,-2 dibutylaminopropylamino- 4 p nitroanilino 6methylpyrimidine, M. P.

Example 43.2 -'Y diethylaminopropylamino- 4 pchloroanilino-5-nitro-6-methy1pyrimidine,

M. P. 109-110 C.

Example 44-2-y-N-methyl-N-isopr0pylaminopropylamino4-p-chloroanilino-5-nitro-6-methylpyrimidine, M. P. 96-98 C.

Example 47.2-p-chloroanilino 4 -p-diethyl- 20 aminoethylamino-S-nitro 6methylpyrimidine, M. P. 146-148 C. and

Example 48.2-p-chloroanilino 4 -diethylaminopropylamino-5-nitroG-methylpyrimidine, M. P. 94-96 C.

Whereas the above description and examples illustrate many widely variedembodiments of the invention it will be apparent to one skilled in theart that many other embodiments and variations may be devised withoutdeparting from the spirit and scope thereof and accordingly it is to beunderstood that the invention is not in any way limited except asdefined in the following claims.

In the claims below the expression lower alkyl" shall be understood asreferring to an alkyl radical having not more than 6 carbon atoms, butwhich may be otherwise straight-chained or branched-chained. Theexpression N-radical" when referring to an amine or nitrogenous basemeans the radical obtained by removing one of the hydrogens (or the onlyhydrogen) from the N-atom of the specified amine or base. The expressionacidic substituents refers to radicals commonly recognized as ionizable,salt-forming, acid radicals.

We claim:

1. A compound selected from the group consisting of the free base form,salts and tautomers of the pyrimidine derivatives which in form of freebase correspond to the following formula where X stands for a member ofthe group consisting of hydrogen, lower alkyl and phenyl; Y is a memberselected from the group consisting of hydrogen, lower alkyl, phenyl,benzyl, phenoxy, halogen and nitro; one of the members G and G is theN-radical of an aromatic amine which contains not more than 10 C-atomsin its cyclic skeleton and whose cyclic carbon atoms have theirextranuclear valencies satisfied by attachment to members selected fromthe group consisting of hydrogen, halogen, lower alkyl, alkoxy,alkyl-thio, alkylamino, carbomethoxy, phenyl, nitro and cyano; while theother of said members G and G represents a strongly basic radical of theform wherein R" stands for a member of the group consisting of hydrogenand methyl, Q is the N- radical of a nitrogenous base selected from thegroup consisting of lower monoalkyl-amines, lower dialkyl amines,piperidine and pyrrolidine, while A is a divalent, saturated, aliphaticradical which interposes between Q and N not less than 2 and not morethan 5 carbon atoms and which has one of the forms: alk, alk--Oalk,

alkNHalk and elk-N-alk "alk being a lower alkyl radical.

2. A compound selected from the group consisting of the free base form,salts and tautomers of the pyrimidine derivatives which in form of freebase correspond to the following formula where X stands for a member ofthe group consisting of hydrogen, lower alkyl and phenyl; Y is a memberselected from the group consisting of sisting of hydrogen, halogen,lower alkyl, alkoxy,

alkyl-thio, alkylamino, carbomethoxy, phenyl, nitro and cyano; while theother of said members G and G represents a strongly basic radical of theform wherein R" stands for a member of the group consisting of hydrogenand methyl, Q is the N- radical of a nitrogenous base selected from thegroup consisting of lower monoalkyl-amines, lower dialkyl amines,piperidine and pyrrolidine, while alk stands for a saturated aliphatichydrocarbon'radical having not less than 2 and not more than 5 carbonatoms.

3. A compound selected from the group consisting of the free base form,salts and tautomers of the pyrimidine derivatives which in form of freebase correspond to the following formula N=CX G- Y II II N-o-o' where Xstands for a member of the group consisting of hydrogen, lower alkyl andphenyl; Y is a member selected from the group consisting of hydrogen,lower alkyl, phenyl, benzyl, phenoxy, halogen and nitro; one of themembers G and G is the N-radical of an aromatic amine which contains notmore than C-atoms in its cyclic skeleton and whose cyclic carbon atomshave their extranuclear valencies satisfied by attachment to membersselected from the group consisting of hydrogen, halogen, lower alkyl,alkoxy, alkyl-thio, alkylamino, carbomethoxy, phenyl, nitro and cyano;while the other of said members G and G represents a strongly basicradical of the form wherein R and R are lower alkyl radicals, while alkstands for a saturated aliphatic hydrocarbon radical having not lessthan 2 and not more than 5 carbon atoms.

4. A compound selected from the group consisting of the free base form,salts and tautomers of the pyrimidine derivatives which in form of freebase correspond to the following'formula where X stands for a member ofthe group consisting of hydrogen, lower alkyl and phenyl; Y is a memberselected from the group consisting of hydrogen, lower alkyl, phenyl,benzyl, phenoxy, halogen and nitro; Am is the N-radical of an aromaticamine which contains not more than 10 C-atoms in its cyclic skeleton andwhose cyclic carbon atoms have their extranuclear valencies satisfied byattachment to members selected from the group consisting of hydrogen,halogen, lower 22 alkyl, alkoxy, alkyl-thio, alkylamino, carbomethoxy,phenyl, nitro and cyano; while G represents a strongly basic radical ofthe form wherein R" stands for a member of the group consisting ofhydrogen and methyl, Q is the N- radical of a nitrogenous base selectedfrom the group consisting of lower monoalkyl-amines, lower dialkylamines, piperidine and pyrrolidine, while A is a divalent, saturated,aliphatic radical which interposes between Q and N not less than 2 andnot more than 5 carbon atoms and which has one of the forms: alk,alkO--alk,

alk-NHalk and alk-N-alk all:

alk being a lower alkyl radical.

5. A compound selected from the group consisting of the free base form,salts and tautomers of the pyrimidine derivatives which in form of freebase correspond to the following formula where X stands for a member ofthe group consisting of hydrogen, lower alkyl and phenyl; Y is a memberselected from the group consisting of hydrogen, lower alkyl, phenyl,benzyl, phenoxy, halogen and nitro; Am is the N-radical of an aromaticamine which contains not more than 10 C-atoms in its cyclic skeleton andwhose cyclic carbon atoms have their extranuclear valencies satisfied byattachment to members selected from the group consisting of hydrogen,halogen, lower alkyl, alkoxy, alkyl-thio, alkylamino, carbomethoxy,phenyl, nitro and cyano; while G represents a strongly basic radical ofthe form wherein R" stands for a member of the group consisting ofhydrogen and methyl, Q is the N- radical of a nitrogenous base selectedfrom the group consisting of lower monoalkyl-amines, lower dialkylamines, piperidine and pyrrolidine, while all: stands for a saturatedaliphatic hydrocarbon radical having not less than 2 and not more than 5carbon atoms.

6. A compound selected from the group consisting of the free base form,salts and tautomers of the pyrimidine derivatives which in form of freebase correspond to the following formula where X stands for a member ofthe group consisting of hydrogen, lower alkyl and phenyl; Y is a memberselected from the group consisting of hydrogen, lower alkyl, phenyl,benzyl, phenoxy, halogen and nitro; Am is the N-radical of an aromaticamine which contains not more than 10 C-atoms in its cyclic skeleton andwhose cyclic carbon atoms have their extranuclear valencies satisfied byattachment to members selected from the group consisting of hydrogen,halogen, lower alkyl, alkoxy, alkyl-thio, alkylamino, carbo- 23'methoxy, phenyl, nitro and oyano; while G represents a strongly basicradical of the form wherein R and R are lower alkyl radicals, while alkstands for a saturated aliphatic hydrocarbon radical having not lessthan 2 and not more than 5 carbon atoms.

7. A compound selected from the group consisting of the free base forms,salts and. tautomers of the pyrimidine derivatives which in form of freebase correspond to the following formula wherein X stands for a memberof the group consisting of hydrogen, lower alkyl and phenyl; Am is theN-radical of an aromatic amine which contains not more than C-atoms inits cyclic skeleton and whose cyclic carbon atoms have theirextranuclear valencies satisfied by attachment to members selected fromthe group consisting of hydrogen, halogen, lower alkyl, alkoxy,alkyl-thio, alkylamino, carbomethoxy, phenyl, nitro and cyano; R and Rare lower alkyl radicals, while alk stands for a saturated alpihatichydrocarbon radical having not less than 2 and not more than 5 carbonatoms.

8. A compound selected from the group consisting of the free baseform,salts and tautomers of the pyrimidine derivatives which in form of freebase correspond to the following formula R N--C-Am wherein Am is theN-radical of an aromatic amine which contains not more than 10 C-atomsin its cyclic skeleton and whose cyclic carbon atoms have theirextranuclear valencies satisfied by attachment to members selected fromthe 24 group consisting of hydrogen, halogen, lower alkyl, alkoxy,alkyl-thio, alkylamino, carbomethoxy, phenyl, nitro and cyano; R and Rare lower alkyl radicals, while alk stands for a saturated aliphatichydrocarbon radical having not less than 2 and not more than 5 carbonatoms.

9. As new pyrimidine compounds theZ-dialkylamino-alkylamino-G-methylpyrimidines bearing in the 4-positionan arylamino radical devoid of acidic substituents.

10. As new compounds the 4-p-halogenoanilino 6-methyl-2-dialkylaminoalkylaminopyrimidines.

11. As a new compound 2- -dibutylaminopropylamino-4-p-chloroanilino-6methylpyrimidine.

12. As a new compound Z- -piperidinOprQpyI-amino-4-p-chloroanilino-6-methylpyrimidine.

13. As a new compound2-y-piperidinopropylamino-l-p-nitroanilino-6-methylpyrimidine.

14. A process for producing the organic compounds defined in claim 1,which comprises reacting a diamine of formula Q-A--NHR", wherein Q, R"and A have the same significance as in claim 1, with a pyrimidinederivative as therein defined except that it carries a labile group inlieu of the substituent G.

15. A process for producing the organic compounds defined in claim 5,which comprises reacting a diamine of formula Qa1k-NHR", wherein Q, Rand alk have the same significance as in claim 5, with a pyrimidinederivative as therein defined except that it carries a halogen atom inposition 2, in lieu of the substituent G therein indicated.

16. A process for producing the organic compounds defined in claim 7,which comprises reacting a dialkylamino-alkylamine with a 2-chloro-pyrimidine bearing in the 4-position an arylamino radical asdefined in claim 7 and in the 6-position a substituent X as thereindefined.

FRANCIS HENRY SWINDEN CURD. CLIFFORD GORDON RAISON. FRANCIS LESLIE ROSE.

